How Double Stress Alters the Brain and Behavior of Mice

Experiencing trauma is bad enough, but if you are already under constant stress before the birth, you may be going through an especially difficult time. Our emotions can be affected by infections in the womb. This can result in double stress, where infection during pregnancy is followed by social stress during postpartum development.

Double Stress and its Consequences

A team of researchers at Kyoto University recently set out to understand the mechanisms by which double stress leads to brain dysfunction and mental disorders. They conducted a comprehensive study of the social and cognitive behavior of mice exposed to such stress, paying particular attention to anxiety-like behaviors. This team had previously demonstrated that acute inflammation in the cerebellum caused by a bacterial infection induces neural plasticity, which in turn can lead to brain hyperexcitability and the appearance of depressive and autism-like symptoms. However, it remained unclear exactly how double stress contributes to brain changes.

The test mice in the current study were allowed to move freely, which led to significant behavioral differences in the mice with dual stress that correlated with abnormalities in the cerebellum. Specifically, the researchers observed a significant increase in the number and turnover of microglia, the primary immune cells in the central nervous system. The study also showed neuronal loss in the cerebellum, a reduction in the action potential of the remaining cerebellar neurons, and a decrease in brain-wide functional connectivity. Exposure to this stress altered microglial reactivity in the cerebellum of both male and female mice, leading to cerebellar dysfunction and behaviors similar to psychiatric disorders.

Personalized Medicine in the Field of Mental Health

But there is also good news. To save the stressed mice, the researchers used microglia replacement to mitigate the effects of the double stress. Suppressing microglia can also be effective, but systemic depletion of microglia usually weakens immunity and makes the body more susceptible to infections. To address this limitation, the team performed cerebellum-specific microglia replacement, which worked remarkably well. The researchers were impressed to see that the female mice showed significantly greater stress resistance.

This suggests that in some animals, under certain conditions, there are sex differences in the response to chronic inflammatory stress in the cerebellum. Consequently, personalized medicine in mental health may require considering sex/gender as an important factor, which could also be applied to neurodegenerative diseases and the treatment of aging. Overall, these results provide new avenues for understanding the biological mechanisms underlying mental disorders and have the potential to change both scientific approaches and societal attitudes towards supporting those affected.